Brand Names: U.S.

Pharmacologic Category

Pharmacology

Immunomodulatory and antiangiogenic characteristics; immunologic effects may vary based on conditions; may suppress excessive tumor necrosis factor-alpha production in patients with ENL, yet may increase plasma tumor necrosis factor-alpha levels in HIV-positive patients. In multiple myeloma, thalidomide is associated with an increase in natural killer cells and increased levels of interleukin-2 and interferon gamma. Other proposed mechanisms of action include suppression of angiogenesis, prevention of free-radical-mediated DNA damage, increased cell mediated cytotoxic effects, and altered expression of cellular adhesion molecules.

Absorption

Slow, good

Distribution

Vd: 1.1 L/kg

Metabolism

Minimal (unchanged drug is the predominant circulating component)

Excretion

Urine (~92%; <4% of the dose as unchanged drug); feces (<2%)

Time to Peak

Plasma: ~2 to 5 hours

Half-Life Elimination

5.5 to 7.3 hours

Protein Binding

55% to 66%

Special Populations Note

Hansen disease:

Based on data from a small study, in relation to healthy subjects, patients with Hansen disease may have increased thalidomide bioavailability, manifested as increased area under the curve and peak plasma levels.

Off Label Uses

AIDS-related aphthous stomatitis

Data from a double-blind, randomized, placebo-controlled trial in HIV-infected patients with oral aphthous ulcers supports the use of thalidomide for this condition [Jacobson 1997].

Chronic graft-versus-host disease, refractory (adults)

Data from two trials evaluating the use of thalidomide for the treatment of patients with high-risk or refractory chronic graft-versus-host disease (GVHD) suggests that thalidomide may be beneficial for the treatment of this condition [Parker 1995], [Vogelsang 1992]. Data from a prospective trial evaluating patients with refractory acute or chronic GVHD supports the use of thalidomide in the treatment of chronic GVHD; no activity was seen in patients with acute GVHD [Kulkarni 2003]. Additional data may be necessary to further define the role of thalidomide in this condition.

Chronic graft-versus-host disease, refractory (children)

Data from a preliminary trial evaluating the use of thalidomide for the treatment of patients with high-risk chronic graft-versus-host disease (GVHD) suggests that thalidomide may be beneficial for the treatment of this condition [Vogelsang 1992]. Data from a limited number of pediatric patients with high-risk and/or refractory chronic GVHD also suggest that thalidomide may be beneficial for the treatment of this condition [Rovelli 1998]. Additional data may be necessary to further define the role of thalidomide in this condition.

Multiple myeloma, maintenance

Data from a large randomized phase III trial and a retrospective analysis support the use of thalidomide for maintenance therapy after autologous stem cell transplantation [Brinker 2006], [Spencer 2009].

Multiple myeloma, salvage

Multiple clinical studies have supported the use of thalidomide (alone or in combination with dexamethasone or other cytotoxic chemotherapy) in the treatment of relapsed/refractory multiple myeloma [Garderet 2012], [Lee 2003], [Palumbo 2001], [Singhal 1999].

Systemic light chain amyloidosis

Data from a trial evaluating the use thalidomide in patients with advanced systemic light chain amyloidosis suggests that thalidomide may be beneficial for the treatment of this condition [Wechalekar 2007]. Additional data may be necessary to further define the role of thalidomide in this condition.

Uremic pruritus, refractory

Data regarding thalidomide, a recognized teratogen, in the treatment of pruritus are limited. Despite apparent benefits observed in a small number of patients, several other treatment modalities with more benign safety profiles are available. Additional data may be necessary to further define the role of thalidomide in this condition.

The European Dermatology Forum and European Academy of Dermatology and Venereology guidelines on the management of chronic pruritus state that though there is evidence for antipruritic effect, thalidomide is not recommended for the treatment of chronic pruritus due to its adverse effects.

Waldenström macroglobulinemia

Data from a phase II study in patients with symptomatic Waldenström macroglobulinemia suggests that thalidomide may be beneficial in the treatment of this condition [Treon 2008]. Additional data may be necessary to further define the role of thalidomide in this condition.

Contraindications

Hypersensitivity to thalidomide or any component of the formulation; pregnancy

Canadian labeling: Additional contraindications (not in the US labeling): Hypersensitivity to lenalidomide or pomalidomide; females at risk of becoming pregnant and male patients who are unable to follow or comply with conditions for use (refer to manufacturer labeling); breast-feeding

Dosing: Adult

Erythema nodosum leprosum, acute cutaneous: Oral: Initial: 100 to 300 mg once daily at bedtime, continue until signs/symptoms subside (usually ~2 weeks), then taper off in 50 mg decrements every 2 to 4 weeks. For severe cases with moderate to severe neuritis, corticosteroids may be initiated with thalidomide (taper off and discontinue corticosteroids when neuritis improves).

Patients weighing <50 kg: Initiate at lower end of the dosing range

Severe cutaneous reaction or patients previously requiring high doses: May be initiated at up to 400 mg once daily at bedtime or in divided doses

Erythema nodosum leprosum, maintenance (prevention/suppression, or with flares during tapering attempts): Oral: Maintain on the minimum dosage necessary to control the reaction; efforts to taper off should be attempted every 3 to 6 months, in decrements of 50 mg every 2 to 4 weeks.

In combination with bortezomib and dexamethasone (off-label combination): Induction therapy: 100 mg once daily for the first 14 days, then 200 mg once daily for 3 (21-day) cycles (Cavo 2010) or 100 mg once daily for up to 8 (21-day) cycles (Kaufman 2010)

In combination with melphalan and prednisone (off-label combination): 200 to 400 mg once daily (Facon 2007) or 100 mg once daily (Palumbo 2008) or 50 to 100 mg once daily, depending on patient tolerance (Hulin 2009)

Uremic pruritus, refractory (off-label use): Oral: 100 mg once daily at bedtime (Silva 1994). Additional data is necessary to further define the role of thalidomide in this condition; several other treatment modalities with more benign safety profiles are available.

Dosing: Renal Impairment

No dosage adjustment necessary for patients with renal impairment and on dialysis (per manufacturer). In a study of 6 patients with end-stage renal disease on dialysis, although clearance was increased by dialysis, a supplemental dose was not needed (Eriksson 2003).

Multiple myeloma: An evaluation of 29 newly diagnosed myeloma patients with renal failure (serum creatinine ≥2 mg/dL) treated with thalidomide and dexamethasone (some also received cyclophosphamide) found that toxicities and efficacy were similar to patients with normal renal function (Seol 2010). A study evaluating induction therapy with thalidomide and dexamethasone in 31 newly diagnosed myeloma patients with renal failure (CrCl <50 mL/minute), including 16 patients with severe renal impairment (CrCl <30 mL/minute) and 7 patients on chronic hemodialysis found that toxicities were similar to patients without renal impairment and that thalidomide and dexamethasone could be administered safely (Tosi 2009). The International Myeloma Working Group (IMWG) suggests that thalidomide may be safely administered to patients with renal impairment, including those on dialysis (Dimopoulos 2016). The IMWG recommends the use of the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation (preferred) or the Modification of Diet in Renal Disease (MDRD) formula to evaluate renal function estimation in multiple myeloma patients with a stable serum creatinine.

Dosing: Hepatic Impairment

There are no dosage adjustments provided in the manufacturer’s labeling (has not been studied). However, thalidomide does not appear to undergo significant hepatic metabolism.

Extemporaneously Prepared

A 20 mg/mL oral suspension may be prepared with capsules and a 1:1 mixture of Ora-Sweet and Ora-Plus. Empty the contents of twelve 100 mg capsules into a glass mortar. Add small portions of the vehicle and mix to a uniform paste; mix while adding the vehicle in incremental proportions to almost 60 mL; transfer to an amber calibrated bottle, rinse mortar with vehicle, and add quantity of vehicle sufficient to make 60 mL. Label “shake well,” “protect from light,” and “refrigerate”. Stable for 35 days refrigerated.

Administration

Administer orally, preferably at bedtime once daily, at least 1 hour after the evening meal. Doses >400 mg/day may be given in divided doses at least 1 hour after meals. Swallow capsules whole with water. Capsules should not be opened or crushed.

Capsules should remain in blister pack until ingestion. If exposed to the powder content from broken capsules or body fluids from patients receiving thalidomide, the exposed area should be washed immediately and thoroughly with soap and water.

Missed doses: For missed doses, if <12 hours patient may receive dose; if >12 hours wait until next dose due.

Storage

Store at 20°C to 25°C (68°F to 77°F); excursions are permitted between 15°C and 30°C (59°F and 86°F). Protect from light. Keep in original package.

Drug Interactions

Abatacept: Anti-TNF Agents may enhance the adverse/toxic effect of Abatacept. An increased risk of serious infection during concomitant use has been reported. Avoid combination

Amifostine: Blood Pressure Lowering Agents may enhance the hypotensive effect of Amifostine. Management: When amifostine is used at chemotherapy doses, blood pressure lowering medications should be withheld for 24 hours prior to amifostine administration. If blood pressure lowering therapy cannot be withheld, amifostine should not be administered. Consider therapy modification

Anakinra: Anti-TNF Agents may enhance the adverse/toxic effect of Anakinra. An increased risk of serious infection during concomitant use has been reported. Avoid combination

Bisphosphonate Derivatives: Angiogenesis Inhibitors (Systemic) may enhance the adverse/toxic effect of Bisphosphonate Derivatives. Specifically, the risk for osteonecrosis of the jaw may be increased. Monitor therapy

Leflunomide: Immunosuppressants may enhance the adverse/toxic effect of Leflunomide. Specifically, the risk for hematologic toxicity such as pancytopenia, agranulocytosis, and/or thrombocytopenia may be increased. Management: Consider not using a leflunomide loading dose in patients receiving other immunosuppressants. Patients receiving both leflunomide and another immunosuppressant should be monitored for bone marrow suppression at least monthly. Consider therapy modification

Pembrolizumab: May enhance the adverse/toxic effect of Thalidomide Analogues. Specifically, mortality may be increased when this combination is used for treatment of refractory multiple myeloma. Avoid combination

Vaccines (Live): Immunosuppressants may enhance the adverse/toxic effect of Vaccines (Live). Immunosuppressants may diminish the therapeutic effect of Vaccines (Live). Management: Avoid use of live organism vaccines with immunosuppressants; live-attenuated vaccines should not be given for at least 3 months after immunosuppressants. Avoid combination

ALERT: U.S. Boxed Warning

Pregnancy:

If thalidomide is taken during pregnancy, it may cause severe birth defects or embryo-fetal death. Thalidomide should never be used by females who are pregnant or who could become pregnant while taking thalidomide. Even a single dose (1 capsule [regardless of strength]) taken by a pregnant woman during pregnancy may cause severe birth defects.

Because of this toxicity and in an effort to make the chance of embryo-fetal exposure to thalidomide as negligible as possible, thalidomide is approved for marketing only through a special restricted distribution program: Thalomid REMS program, approved by the Food and Drug Administration. Information about Thalomid and the Thalomid REMS program is available at https://www.celgeneriskmanagement.com or by calling the manufacturer's toll-free number 1-888-423-5436.

Thromboembolic events:

The use of thalidomide in multiple myeloma results in an increased risk of venous thromboembolism, such as deep venous thrombosis and pulmonary embolism. This risk increases significantly when thalidomide is used in combination with standard chemotherapeutic agents including dexamethasone. In 1 controlled trial, the rate of venous thromboembolism was 22.5% in patients receiving thalidomide in combination with dexamethasone compared with 4.9% in patients receiving dexamethasone alone (P = 0.002). Patients and physicians are advised to be observant for the signs and symptoms of thromboembolism. Instruct patients to seek medical care if they develop symptoms such as shortness of breath, chest pain, or arm or leg swelling. Consider thromboprophylaxis based on an assessment of individual patients' underlying risk factors.

Warnings/Precautions

Concerns related to adverse effects:

• Bone marrow suppression: May cause leukopenia and neutropenia; avoid initiating therapy if ANC <750/mm3. Persistent neutropenia may require treatment interruption. Thrombocytopenia (including grades 3 and 4) has been reported; may require dose reduction, treatment delay, or discontinuation. Monitor for signs and symptoms of bleeding (including petechiae, epistaxis, and gastrointestinal bleeding), especially if concomitant medication may increase the risk of bleeding. Monitor CBC with differential and platelets. Anemia has also been observed.

• Bradycardia: May cause bradycardia; use with caution when administering concomitantly with medications that may also decrease heart rate. May require thalidomide dose reduction or discontinuation.

• Dermatologic reactions: Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) have been reported (may be fatal); withhold therapy and evaluate if skin rash occurs; permanently discontinue if rash is exfoliative, purpuric, bullous or if SJS or TEN is suspected.

• Hepatotoxicity: Abnormal liver function tests, hepatitis and cholestatic jaundice have been reported. Hepatotoxicity (including hepatocellular and cholestatic injury) has been observed rarely (case reports), with a mean time to development of 46 days; most events resolved after discontinuing thalidomide (Vilas-Boas 2012).

• Hypersensitivity: Hypersensitivity, including erythematous macular rash, possibly associated with fever, tachycardia and hypotension has been reported. May require treatment interruption for severe reactions; discontinue if recurs with rechallenge.

• Orthostatic hypotension: May cause orthostatic hypotension; use with caution in patients who would not tolerate transient hypotensive episodes. When arising from a recumbent position, advise patients to sit upright for a few minutes prior to standing.

• Peripheral neuropathy: Thalidomide is commonly associated with peripheral neuropathy; may be irreversible. Neuropathy generally occurs following chronic use (over months), but may occur with short-term use; onset may be delayed. Use caution with other medications that may also cause peripheral neuropathy. Monitor for signs/symptoms of neuropathy monthly for the first 3 months of therapy and regularly thereafter. Electrophysiological testing may be considered at baseline and every 6 months to detect asymptomatic neuropathy. To limit further damage, immediately discontinue (if clinically appropriate) in patients who develop neuropathy. Reinitiate therapy only if neuropathy returns to baseline; may require dosage reduction or permanent discontinuation.

• Secondary malignancy: Increased incidence of second primary malignancies (SPMs), including acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS), has been observed in previously untreated multiple myeloma patients receiving thalidomide in combination with melphalan, and prednisone. In addition to AML and MDS, solid tumors have been reported with thalidomide maintenance treatment for multiple myeloma (Usmani 2012). Carefully evaluate patients for SPMs prior to and during treatment and manage as clinically indicated.

• Seizures: Seizures (including grand mal convulsions) have been reported in postmarketing data; monitor closely for clinical changes indicating potential seizure activity in patients with a history of seizures, concurrent therapy with drugs that alter seizure threshold, or conditions that predispose to seizures.

• Thromboembolic events: [US Boxed Warning]: Thalidomide use for the treatment of multiple myeloma is associated with an increased risk for venous thromboembolism (VTE), including deep vein thrombosis (DVT) and pulmonary embolism (PE); the risk is increased when used in combination with standard chemotherapy agents, including dexamethasone. In one controlled study, the incidence of VTE was 22.5% in patients receiving thalidomide in combination with dexamethasone, compared to 4.9% for dexamethasone alone. Monitor for signs and symptoms of thromboembolism (shortness of breath, chest pain, or arm or leg swelling) and instruct patients to seek prompt medical attention with development of these symptoms. Consider thromboprophylaxis based on risk factors. Ischemic heart disease, including MI and stroke, also occurred at a higher rate (compared to placebo) in myeloma patients receiving thalidomide plus dexamethasone who had not received prior treatment. Assess individual risk factors for thromboembolism and consider thromboprophylaxis. The American Society of Clinical Oncology guidelines for VTE prophylaxis and treatment recommend thromboprophylaxis for patients receiving thalidomide in combination with chemotherapy and/or dexamethasone; either aspirin or low molecular weight heparin (LMWH) is recommended for lower risk patient and LMWH is recommended for higher-risk patients (Lyman 2013; Lyman 2015). Anticoagulant prophylaxis should be individualized and selected based on the venous thromboembolism risk of the combination treatment regimen, using the safest and easiest to administer (Palumbo 2008). Monitor for signs/symptoms of thromboembolism and advise patients to seek immediate care if symptoms (shortness of breath, chest pain, arm/leg swelling) develop. Other medications that are also associated with thromboembolism should be used with caution.

• Tumor lysis syndrome: Patients with a high tumor burden may be at risk for tumor lysis syndrome; monitor closely; institute appropriate management for hyperuricemia.

Disease-related concerns:

• Heart failure: In a scientific statement from the American Heart Association, thalidomide has been determined to be an agent that may exacerbate underlying myocardial dysfunction (magnitude: minor) (AHA [Page 2016]).

• HIV-infected patients: Thalidomide is associated with increased viral loads in studies conducted prior to the use of antiretroviral therapy. Monitor viral load after the first and third months of therapy, and every 3 months thereafter.

• Pregnancy: [US Boxed Warning]: Thalidomide is contraindicated in pregnant women. Thalidomide may cause severe birth defects or embryo-fetal death if taken during pregnancy. Thalidomide cannot be used in women who are pregnant or may become pregnant during therapy as even a single dose may cause severe birth defects. In order to decrease the risk of fetal exposure, thalidomide is available only through a special restricted distribution program (Thalomid REMS). Use is also contraindicated in women who may become pregnant. Pregnancy must be excluded prior to therapy initiation with 2 negative pregnancy tests. Women of reproductive potential must avoid pregnancy beginning 4 weeks prior to therapy, during therapy, during therapy interruptions, and for ≥4 weeks after therapy is discontinued; two reliable methods of birth control, or abstinence from heterosexual intercourse, must be used. Males taking thalidomide (even those vasectomized) must use a latex or synthetic condom during any sexual contact with women of childbearing potential and for up to 28 days following discontinuation of therapy. Males taking thalidomide must not donate sperm. Some forms of contraception may not be appropriate in certain patients. An intrauterine device (IUD) or implantable contraceptive may increase the risk of infection or bleeding; estrogen containing products may increase the risk of thromboembolism.

Other warnings/precautions:

• Blood donation: Patients should not donate blood during thalidomide treatment and for 4 weeks after therapy discontinuation.

• REMS program: Due to the embryo-fetal risk, thalidomide is only available through a restricted program under the Thalomid REMS program. Prescribers and pharmacies must be certified with the program to prescribe or dispense thalidomide. Patients must sign an agreement and comply with the REMS program requirements.

Monitoring Parameters

CBC with differential, platelets; thyroid function tests (TSH at baseline then every 2 to 3 months during thalidomide treatment [Hamnvik 2011]). Hepatic function tests (periodic; particularly with preexisting hepatic dysfunction or concomitant use of drugs associated with hepatotoxicity). In HIV-seropositive patients: viral load after 1 and 3 months, then every 3 months. Pregnancy testing (sensitivity of at least 50 milliunits/mL) is required 10 to 14 days prior to therapy, within 24 hours prior to initiation of therapy, weekly during the first 4 weeks, then every 4 weeks in women with regular menstrual cycles or every 2 weeks in women with irregular menstrual cycles. Signs of neuropathy monthly for the first 3 months, then periodically during treatment; consider monitoring of sensory nerve application potential amplitudes (at baseline and every 6 months) to detect asymptomatic neuropathy. Monitor for signs and symptoms of thromboembolism (shortness of breath, chest pain, arm/leg swelling), tumor lysis syndrome, bradycardia and syncope; monitor for clinical changes indicating potential seizure activity (in patients with a history of seizure).

Pregnancy Considerations

[US Boxed Warning]: Thalidomide is contraindicated in pregnant women. Thalidomide may cause severe birth defects or embryo-fetal death if taken during pregnancy. Thalidomide cannot be used in women who are pregnant or may become pregnant during therapy as even a single dose may cause severe birth defects. In order to decrease the risk of fetal exposure, thalidomide is available only through a special restricted distribution program (Thalomid REMS). Reproduction studies in animals and data from pregnant women have shown evidence of fetal abnormalities; use is contraindicated in women who are or may become pregnant. Anomalies observed in humans include amelia, phocomelia, bone defects, ear and eye abnormalities, facial palsy, congenital heart defects, urinary and genital tract malformations; mortality in ~40% of infants at or shortly after birth has also been reported.

Women of reproductive potential must avoid pregnancy beginning 4 weeks prior to therapy, during therapy, during therapy interruptions, and for at least 4 weeks after therapy is discontinued. Two forms of effective/reliable contraception or total abstinence from heterosexual intercourse must be used by females who are not infertile or who have not had a hysterectomy. A negative pregnancy test (sensitivity of at least 50 milliunits/mL) 10 to 14 days prior to therapy, within 24 hours prior to beginning therapy, weekly during the first 4 weeks, and every 4 weeks (every 2 weeks for women with irregular menstrual cycles) thereafter is required for women of childbearing potential. Thalidomide must be immediately discontinued for a missed period, abnormal pregnancy test or abnormal menstrual bleeding; refer patient to a reproductive toxicity specialist if pregnancy occurs during treatment.

Thalidomide is also present in the semen of males. Males (even those vasectomized) must use a latex or synthetic condom during any sexual contact with women of childbearing potential and for up to 28 days following discontinuation of therapy. Males taking thalidomide must not donate sperm.

The parent or legal guardian for patients between 12 to 18 years of age must agree to ensure compliance with the required guidelines.

A pregnancy exposure registry has been created to monitor outcomes in females exposed to thalidomide during pregnancy and female partners of male patients and to understand the root cause for the pregnancy. The pregnancy exposure registry may be contacted at 1-888-423-5436. If pregnancy occurs during treatment, thalidomide must be immediately discontinued and the patient referred to a reproductive toxicity specialist. Any suspected fetal exposure to thalidomide must be reported to the FDA via the MedWatch program (1-800-FDA-1088) and to Celgene Corporation (1-888-423-5436).

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience constipation, headache, lack of appetite, nausea, edema, dry skin, fatigue, anxiety, tremors, weight gain or loss, or sexual dysfunction. Have patient report immediately to prescriber signs of infection, signs of bleeding (vomiting blood or vomit that looks like coffee grounds; coughing up blood; hematuria; black, red, or tarry stools; bleeding from the gums; abnormal vaginal bleeding; bruises without a reason or that get bigger; or any severe or persistent bleeding), signs of low calcium (muscle cramps or spasms, numbness and tingling, or seizures), signs of blood clots (numbness or weakness on one side of the body; pain, redness, tenderness, warmth, or swelling in the arms or legs; change in color of an arm or leg; angina; shortness of breath; tachycardia; or coughing up blood), burning or numbness feeling, seizures, dizziness, passing out, tachycardia, bradycardia, loss of strength and energy, signs of tumor lysis syndrome (tachycardia or abnormal heartbeat; any passing out; urinary retention; muscle weakness or cramps; nausea, vomiting, diarrhea or lack of appetite; or feeling sluggish), signs of Stevens-Johnson syndrome/toxic epidermal necrolysis (red, swollen, blistered, or peeling skin [with or without fever]; red or irritated eyes; or sores in mouth, throat, nose, or eyes), signs of a heart attack (angina; pain in arms, back, neck, jaw, or abdomen; shortness of breath; cold sweats; severe dizziness; passing out; severe nausea; or vomiting), or signs of severe cerebrovascular disease (change in strength on one side is greater than the other, difficulty speaking or thinking, change in balance, or vision changes) (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.